I will study the quantitative determinants of drug action in man by examining the clinical pharmacology of the coumarin anticoagulant drugs. The oral anticoagulants are an excellent drug system for evaluating precisely pharmacologic effects in men and correlating them with pharmacokinetic changes of the drug. Specific objectives include: (1) to determine whether long-term anticoagulant therapy in man can be made more stable and less dangerous by using only the R(plus)-warfarin enantiomorph rather than the customary racemic mixture of R, S(plus or minus)-warfarin by proving that interacting drugs like metronidazole (Flagyl), disulfiram (Antabuse), phenylbutazone (Butazolidin), and co-trimoxazole (Septra), are stereoselective and interact only with the more potent S(minus)-warfarin enantiomorph and have little or no effect on the pharmacologic effect or drug levels of R(plus)-warfarin, (2) the determination of the effect of the chemotherapeutic agent co-trimoxazole (trimethoprim and sulfamethoxazole, Septra) on the anticoagulant drug sodium warfarin in man, whether one or both agents in co-trimoxazole augment the anticoagulant effect and whether the co-trimoxazole affects one or both of the optical isomers that make up commercial racemic warfarin; (3) to determine whether the diuretic drug spironolactone (Aldactone) interacts with sodium warfarin in man, as has been reported in animals; (4) The development of a more sensitive and specific assay for warfarin and its metabolic products by use of high-pressure liquid chromatography.